The main objective of this proposal is to build a greater understanding of how the striatal cholinergic system contributes to behavioral flexibility. There is accumulating evidence that neurological and psychiatric disorders that lead to striatal neuropathology, i.e. Parkinson's disease, Huntington's disease and schizophrenia, produce severe deficits in cognitive flexibility. In addition to the common cognitive symptomology, Parkinson's and Huntington's disease patients both exhibit decreases in cholinergic markers in the anterior regions of the caudate and putamen. At present, unknown is what striatal circuitry or neurochemical mechanisms underlie cognitive flexibility. Advances in elucidating the etiology of these disorders and development of effective treatments for the cognitive deficits relies, in part, on identifying the basic neurochemical mechanisms within the striatum that underlie the cognitive functions impaired in Parkinson's and Huntington's disease. The first goal of the proposal is to understand the dynamic changes in acetylcholine output in the dorsomedial and dorsolateral striatum during acquisition and reversal learning of a visual cue discrimination, using in vivo microdialysis with high pressure liquid chromatography. Recent timings in Parkinson's disease patients suggest that anti-cholinergic treatments lead to cognitive flexibility deficits. The second goal of the proposal is to determine whether specific muscarinic receptor subtypes in the dorsomedial striatum contribute to behavioral flexibility. Previous studies found that dopamine activity in the striatum also influences cognitive flexibility. Furthermore, extant research indicates an interaction between the dopaminergic and cholinergic systems in the basal ganglia related to motor behavior. The third goal of the proposal is to determine whether dopamine D1 and/or D2 receptors modulate acetylcholine efflux in the dorsomedial striatum to influence behavioral flexibility. Overall, this approach takes a unique approach in examining the dynamic changes in striatal acetylcholine release during the actual learning and shifting of strategies. The proposed studies will also provide complimentary information on the specific muscarinic receptors that may facilitate behavioral flexibility in the dorsomedial striatum. Moreover, the proposed studies can help unravel the complex interaction of neurotransmitters in specific striatal circuitry as it relates to behavioral flexibility. The findings from these experiments may enable the development of selective and targeted pharmacological interventions to alleviate the cognitive symptomology in Parkinson's and Huntington's disease without producing unwanted motoric side effects. [unreadable] [unreadable]